Method of solubilizing poorly soluble/insoluble active material through formation of oligomer composite

ABSTRACT

Provided is a method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite, in which a structure having a hydrophobic cavity structure is formed by using oligomers derived from two types of hydrophilic natural polymers and a poorly soluble/insoluble component is encapsulated in the cavity structure, and thus, self-aggregation of the poorly soluble/insoluble material is prevented and simultaneously, thermodynamic stability increases to effectively solubilize the poorly soluble/insoluble material. According to the constitution of the present invention, the method may include a first operation of preparing an oligomer composite having a cavity structure formed therein by mixing and dissolving oligomers derived from two types of hydrophilic natural polymers in water, and a second operation of adding a poorly soluble/insoluble material to the oligomer composite to encapsulate the poorly soluble/insoluble material in the hydrophobic cavity structure of the oligomer composite.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a national stage filing of International Application No. PCT/KR2010/007066 which claims priority under 35 U.S.C. 119 and 35 U.S.C. 365 to Korean Patent Application No. 10-2009-0121886 filed on Dec. 9, 2009, which is hereby incorporated by reference in its entirety.

BACKGROUND

The present disclosure relates to a method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite, in which a structure having a hydrophobic cavity structure is formed by using oligomers derived from two types of hydrophilic natural polymers and a poorly soluble/insoluble component is encapsulated in the cavity structure, and thus, self-aggregation of the poorly soluble/insoluble material is prevented and simultaneously, thermodynamic stability increases to effectively solubilize the poorly soluble/insoluble material.

Recently, development of natural ingredients having excellent biocompatibility and biostability as well as excellent biological activity with respect to the human body has become more important in discovering biologically active substances in cosmetics, food, and medicine industries. However, some natural ingredients are unstable under an acidic condition or others are unstable under a basic condition. That is, characteristics of the active ingredients are overall different and methods of sufficiently stabilizing active ingredients in a formulation are still in a development stage.

Therefore, natural ingredients currently having high efficacy and effect are expected to have a large potential value, but about 40% of the foregoing natural ingredients are not even in a development stage due to its low solubility. A process of increasing solubility of such a material poorly soluble in water or an aqueous solution by a certain manipulation is denoted as “solubilization”. A typical technique able to improve solubility and increase absorption of drugs may include a method of using an organic solvent, such as ethanol, or surfactant as an additive, a method of preparing as a salt form when an ionization group is contained, and a method of increasing solubility by adjusting a pH, etc.

Recently, various attempts have also been made to improve typical limitations of poorly soluble/insoluble materials by introducing liposome, microemulsion, cyclodextrin, and nanopowder techniques to solubilize the poorly soluble/insoluble materials.

SUMMARY OF THE INVENTION

Embodiments provide a method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite, in which a structure having a hydrophobic cavity structure is formed by using oligomers derived from two types of hydrophilic natural polymers and a poorly soluble/insoluble component is encapsulated in the cavity structure, and thus, self-aggregation of the poorly soluble/insoluble material is prevented and thermodynamic stability increases to effectively solubilize the poorly soluble/insoluble material.

The technical objects of the present disclosure are not limited to the aforesaid, but other technical objects not described herein will be clearly understood by those skilled in the art from descriptions below.

In one embodiment, a method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite includes: a first operation of preparing an oligomer composite having a cavity structure formed therein by mixing and dissolving oligomers derived from two types of hydrophilic natural polymers in water; and a second operation of adding a poorly soluble/insoluble material to the oligomer composite to encapsulate the poorly soluble/insoluble material in the hydrophobic cavity structure of the oligomer composite.

In another embodiment, the method may further include, after the second operation: a third operation of removing a residual poorly soluble/insoluble material unencapsulated in the oligomer composite by filtration or centrifugation of a reaction solution; and a fourth operation of removing water and an organic solvent (when used) from the reaction solution having the residual material removed therefrom to dry.

The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a structure, in which a poorly soluble/insoluble material is encapsulated in a cavity structure of an oligomer composite of the present invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Reference will now be made in detail to the embodiments of the present disclosure, examples of which are illustrated in the accompanying drawings.

A basic concept of the present invention is that when poorly soluble/insoluble materials are encapsulated in an oligomer composite having a hydrophobic cavity structure, precipitation of poorly soluble/insoluble components in an aqueous solution is prevented by preventing aggregation and re-aggregation of the poorly soluble/insoluble components, dissolution stability is improved such that a chemical reaction able to change a structure of the poorly soluble/insoluble components is not accompanied, and these components are encapsulated in an oligomer structure having a cavity structure physically formed therein to maintain an inherent natural biological activity as it is.

A method of preparing an oligomer composite according to the present invention includes: a first operation of preparing an oligomer composite having a physical cavity structure formed therein by mixing and dissolving oligomers derived from two types of hydrophilic natural polymers in water; and a second operation of adding a poorly soluble/insoluble material to the oligomer composite to encapsulate the poorly soluble/insoluble material in the hydrophobic cavity structure of the oligomer composite.

Two natural polymer oligomers are selected from the group consisting of xanthan gum, acacia gum, guar gum, arabic gum, agar, alginic acid, chitosan, pectin, carboxyalkylcellulose, maltodextrin, dextrin, and hyaluronic acid, and then mixed.

Each weight ratio of two types of the selected natural polymer oligomers with respect to distilled water is in a range of 1:1 to 1:10 and in particular, may be in a range of 1:2 to 1:4. At this time, when the weight ratio of one natural polymer oligomer among the two types of natural polymer oligomers is too high, an encapsulation effect of a poorly soluble/insoluble active component may decrease because the hydrophobic cavity structure of the oligomer structure may not be properly formed.

Also, a weight ratio between the two types of natural polymer oligomers and water is in a range of 1:1 to 1:100. When the weight ratio of the natural polymer oligomers with respect to the water is too high, preparation of an oligomer composite solution may be difficult because viscosity of the solution may be excessively increased by the natural polymer oligomers. On the other hand, when the weight ratio of the natural polymer oligomers with respect to the water is too low, the encapsulation effect of the poorly soluble/insoluble active component may decrease because the hydrophobic cavity structure may not be properly formed due to a relatively low physical bonding force between molecules of the oligomer composite in the aqueous solution. An average molecular weight of the natural polymer oligomer used may be in a range of 1,000 to 100,000.

Also, a preparation temperature during the preparation of the oligomer composite may be within a range of 20° C. to 80° C., and in particular, the oligomer composite may be prepared within a temperature range of 40° C. to 50° C. At this time, a pH of the solution may be maintained in a range of 5 to 8. When the pH and temperature during the preparation of the oligomer composite are not controlled, the hydrophobic cavity structure may not be properly formed, because the physical bonding force between the molecules of the oligomer composite may decrease.

Meanwhile, in the second operation of adding a poorly soluble/insoluble material to the oligomer composite to encapsulate the poorly soluble/insoluble material in the hydrophobic cavity structure of the oligomer composite, the poorly soluble/insoluble material may be simply added or may be added by being dissolved in an organic solvent or the like. The poorly soluble/insoluble material is slowly added to the oligomer composite solution formed in the first operation in an amount range of 0.1 wt % to 99 wt % based on a total solid content. At this time, the poorly soluble/insoluble material may be added in an amount range of 1 wt % to 20 wt %. When the poorly soluble/insoluble material is added in an amount more than 99 wt %, an effect of improving solubility of the poorly soluble/insoluble component may decrease, because it deviates from the capacity limit of the hydrophobic cavity structure in the oligomer composite which may encapsulate the poorly soluble/insoluble component.

When the poorly soluble/insoluble material is added in the second operation, an appropriate temperature is within a range of 20° C. to 80° C., and the poorly soluble/insoluble material may be mixed and stirred within a temperature range of 40° C. to 50° C. At this time, an appropriate pH is in a range of 5 to 8 and the pH may be maintained in a range of 6.5 to 7.5. When the temperature and pH are not controlled, the poorly soluble/insoluble active component may not be properly encapsulated in the oligomer composite, because the hydrophobic cavity structure may collapse due to a decrease in the physical bonding force between the natural polymer oligomers constituting the oligomer composite.

Also, the organic solvent may be selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran (THF), and acetonitrile (AN).

The poorly soluble/insoluble materials may be selected from the group consisting of polyphenols, such as amentoflavone, ellagic acid, apigenin, berginin, diosmetin, univestin, resveratrol, isoflavones, and catechin, oily fatty acids, such as salicylic acid, alpha lipoic acid, caffeine, tocopherol, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and conjugated linolenic acid (CLA), and natural extracts containing a ginkgo biloba leaf extract, a red ginseng extract, and polyphenols.

Meanwhile, after the second operation, the method may further include a third operation of removing a residual poorly soluble/insoluble material unencapsulated in the oligomer composite by filtration or centrifugation of a reaction solution and a fourth operation of removing water and an organic solvent (when used) from the reaction solution having the residual material removed therefrom to dry.

The poorly soluble/insoluble materials are introduced to the oligomer composite having the cavity structure to increase the solubility of the poorly soluble/insoluble components and thus, dissolution stability may be improved.

In the present invention, interaction between the two types of natural polymer oligomers is used to form the oligomer composite having hydrophobic cavities and thus, structural density and physical bonding strength may increase. Therefore, the solubility is improved by encapsulating a material having poorly soluble/insoluble characteristics by physical bonding. [see FIG.1]

Hereinafter, the present invention will be described in detail, according to specific examples. However, the following examples are merely presented to exemplify the present invention, and the scope of the present invention is not limited thereto.

CONTROL GROUP EXAMPLES 1 TO 12

One type of natural polymer oligomers was selected and added to 156 g of distilled water according to a ratio of the following Table 1. A reaction temperature was maintained in a range of 40° C. to 50° C., a pH was maintained in a range of 5 to 8 by using a pH adjuster, and an oligomer aqueous solution was formed by being stirred until the oligomer was completely dissolved.

The temperature and pH of the formed oligomer aqueous solution were maintained in ranges of 40° C. to 50° C. and 6.5 to 7.5, respectively. An ellagic acid was used as a representative poorly soluble/insoluble material and a predetermined amount of the ellagic acid was slowly added to the oligomer aqueous solution. The ellagic acid was mixed and stirred within a temperature range of 40° C. to 50° C. At this time, the pH was maintained in a range of 6.5 to 7.5 to allow the ellagic acid to be completely mixed in the oligomer aqueous solution. The prepared aqueous solution was centrifuged and filtered to measure an amount of precipitates, and a filtrate was powdered by using a freeze dryer to prepare a control group.

TABLE 1 Use amount of Use amount Natural polymer from natural polymer of ellagic Control Group which oligomer is derived oligomer acid Example derived (g) (g) Control Group Maltodextrin 40 4 Example 1 Control Group Dextrin 40 4 Example 2 Control Group Guar gum 40 4 Example 3 Control Group Arabic gum 40 4 Example 4 Control Group Acacia gum 40 4 Example 5 Control Group Alginic acid 40 4 Example 6 Control Group Chitosan 40 4 Example 7 Control Group Carboxymeth- 40 4 Example 8 ylcellulose Control Group Pectin 40 4 Example 9 Control Group Agar 40 4 Example 10 Control Group Xanthan gum 40 4 Example 11 Control Group Hyaluronic acid 40 4 Example 12

[Experimental Method for Evaluating Solubility and Dissolution Stability of Control Group]

The ellagic acid was added to the solutions having the natural polymer oligomers dissolved therein and mixed during the preparation of the powders of control group in Control Group Examples 1 to 12, and then the precipitates were dried during centrifugation to measure weights of insoluble precipitates.

The prepared powders of the control group were weighed and put into distilled water to make a volume of 100 ml, and aqueous solutions were then prepared by stirring for 30 minutes. The prepared aqueous solutions were put into centrifuge tubes, in which the weights thereof had been previously measured, and centrifuged. Filtrates were removed and the tubes were dried in a vacuum drier at 60° C. for five days, and amounts of precipitates were then measured by measuring weight changes and solubilities of the oligomer composites containing a poorly soluble/insoluble material with respect to water were calculated. The presence of precipitates were visually observed while the centrifuged supernatants were stored at 4° C. for zero week, one week, two weeks, three weeks, and four weeks.

The result of improvements in the solubility of poorly soluble/insoluble material and the presence of precipitates with respect to control group examples are presented in Table 2.

TABLE 2 Input amount of powders Precipitate of amount control Precipitate Poorly during group amount Control soluble/ preparation during during Group insoluble of control redissolution redissolution Solubility Storage Presence of Example material group (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Control Ellagic 1.90 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 1 Control Ellagic 1.90 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 2 Control Ellagic 1.95 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 3 Control Ellagic 1.94 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 4 Control Ellagic 1.95 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 5 Control Ellagic 1.93 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 6 Control Ellagic 1.95 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 7 Control Ellagic 1.96 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 8 Control Ellagic 1.95 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 9 Control Ellagic 1.92 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 10 Control Ellagic 1.90 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 11 Control Ellagic 1.91 2.0 0.0 20.0 4 weeks Occurred in Group acid one week Example 12 ¹⁾precipitate amount of ellagic acid undissolved during the preparation of single oligomer composite containing an ellagic acid ²⁾storage period of 4 weeks at 4° C., observation of the presence of precipitate

As shown in the result of Table 2, with respect to the control group examples in which single natural polymer oligomer was used, it may be understood that most of ellagic acid were precipitated instead of being unencapsulated in the single natural polymer oligomer during the oligomer powders containing the ellagic acid were dissolved in water and centrifuged. In order to investigate whether or not the solubilities were improved, the powders of the control group were redissolved and centrifuged, and then weights of precipitates were measured. As a result, the precipitates were not confirmed, but a residual ellagic acid was precipitated in one week when the centrifuged supernatant was stored at 4° C. and thus, it may be understood that the control group did not affect the improvement of the solubility of poorly soluble/insoluble component and the dissolution stability.

EXAMPLES 1 TO 120 Application of Oligomer Derived from Natural Polymer

Two types of natural polymer oligomers were mixed and added to 156 g of distilled water according to a ratio of the following Tables 3 to 5. A reaction temperature was maintained in a range of 40° C. to 50° C., a pH was maintained in a range of 5 to 8 by using a pH adjuster, and an oligomer composite solution was formed by stirring until the oligomers were completely dissolved.

Temperature and pH of the formed oligomer composite solution were maintained in ranges of 40° C. to 50° C. and 6.5 to 7.5, respectively. An ellagic acid was used as a representative poorly soluble/insoluble material and a predetermined amount of the ellagic acid was slowly added to the oligomer composite solution. The ellagic acid was mixed and stirred within a temperature range of 40° C. to 50° C. At this time, the pH was maintained in a range of 6.5 to 7.5 to allow the ellagic acid to be encapsulated in the hydrophobic cavity structure of the oligomer composite. The reaction solution was centrifuged and filtered to measure weight of the unencapsulated and removed ellagic acid, and a supernatant or filtrate was powdered by using a freeze dryer to prepare an ellagic acid encapsulated oligomer composite.

TABLE 3 Use amount of Natural polymer from Use ellagic which oligomer is amount acid Example derived (g) (g) Example 1 Xanthan gum 10 4 Maltodextrin 30 Example 2 Xanthan gum 10 4 Dextrin 30 Example 3 Xanthan gum 10 4 Guar gum 30 Example 4 Xanthan gum 10 4 Arabic gum 30 Example 5 Xanthan gum 10 4 Acacia gum 30 Example 6 Xanthan gum 10 4 Alginic acid 30 Example 7 Xanthan gum 10 4 Chitosan 30 Example 8 Xanthan gum 10 4 Carboxymethylcellulose 30 Example 9 Xanthan gum 10 4 Pectin 30 Example Xanthan gum 10 4 10 Agar 30 Example Maltodextrin 10 4 11 Xanthan gum 30 Example Maltodextrin 10 4 12 Dextrin 30 Example Maltodextrin 10 4 13 Guar gum 30 Example Maltodextrin 10 4 14 Arabic gum 30 Example Maltodextrin 10 4 15 Acacia gum 30 Example Maltodextrin 10 4 16 Alginic acid 30 Example Maltodextrin 10 4 17 Chitosan 30 Example Maltodextrin 10 4 18 Carboxymethylcellulose 30 Example Maltodextrin 10 4 19 Pectin 30 Example Maltodextrin 10 4 20 Agar 30 Example Dextrin 10 4 21 Maltodextrin 30 Example Dextrin 10 4 22 Xanthan gum 30 Example Dextrin 10 4 23 Guar gum 30 Example Dextrin 10 4 24 Arabic gum 30 Example Dextrin 10 4 25 Acacia gum 30 Example Dextrin 10 4 26 Alginic acid 30 Example Dextrin 10 4 27 Chitosan 30 Example Dextrin 10 4 28 Carboxymethylcellulose 30 Example Dextrin 10 4 29 Pectin 30 Example Dextrin 10 4 30 Agar 30 Example Guar gum 10 4 31 Maltodextrin 30 Example Guar gum 10 4 32 Dextrin 30 Example Guar gum 10 4 33 Xanthan gum 30 Example Guar gum 10 4 34 Arabic gum 30 Example Guar gum 10 4 35 Acacia gum 30 Example Guar gum 10 4 36 Alginic acid 30 Example Guar gum 10 4 37 Chitosan 30 Example Guar gum 10 4 38 Carboxymethylcellulose 30 Example Guar gum 10 4 39 Pectin 30 Example Guar gum 10 4 40 Agar 30 Example Arabic gum 10 4 41 Maltodextrin 30 Example Arabic gum 10 4 42 Dextrin 30 Example Arabic gum 10 4 43 Guar gum 30 Example Arabic gum 10 4 44 Xanthan gum 30 Example Arabic gum 10 4 45 Acacia gum 30 Example Arabic gum 10 4 46 Alginic acid 30 Example Arabic gum 10 4 47 Chitosan 30 Example Arabic gum 10 4 48 Carboxymethylcellulose 30

TABLE 4 Use amount of Natural polymer from Use ellagic which oligomer is amount acid Example derived (g) (g) Example Arabic gum 10 4 49 Pectin 30 Example Acacia gum 10 4 50 Maltodextrin 30 Example Acacia gum 10 4 51 Dextrin 30 Example Acacia gum 10 4 52 Guar gum 30 Example Acacia gum 10 4 53 Arabic gum 30 Example Acacia gum 10 4 54 Xanthan gum 30 Example Acacia gum 10 4 55 Alginic acid 30 Example Acacia gum 10 4 56 Chitosan 30 Example Acacia gum 10 4 57 Carboxymethylcellulose 30 Example Acacia gum 10 4 58 Pectin 30 Example Acacia gum 10 4 59 Agar 30 Example Alginic acid 10 4 60 Maltodextrin 30 Example Alginic acid 10 4 61 Dextrin 30 Example Alginic acid 10 4 62 Guar gum 30 Example Alginic acid 10 4 63 Arabic gum 30 Example Alginic acid 10 4 64 Acacia gum 30 Example Alginic acid 10 4 65 Xanthan gum 30 Example Alginic acid 10 4 66 Chitosan 30 Example Alginic acid 10 4 67 Carboxymethylcellulose 30 Example Alginic acid 10 4 68 Pectin 30 Example Alginic acid 10 4 69 Agar 30 Example Chitosan 10 4 70 Maltodextrin 30 Example Chitosan 10 4 71 Dextrin 30 Example Chitosan 10 4 72 Guar gum 30 Example Chitosan 10 4 73 Arabic gum 30 Example Chitosan 10 4 74 Acacia gum 30 Example Chitosan 10 4 75 Alginic acid 30 Example Chitosan 10 4 76 Xanthan gum 30 Example Chitosan 10 4 77 Carboxymethylcellulose 30 Example Chitosan 10 4 78 Pectin 30 Example Chitosan 10 4 79 Agar 30 Example Carboxymethylcellulose 10 4 80 Maltodextrin 30 Example Carboxymethylcellulose 10 4 81 Dextrin 30 Example Carboxymethylcellulose 10 4 82 Guar gum 30 Example Carboxymethylcellulose 10 4 83 Arabic gum 30 Example Carboxymethylcellulose 10 4 84 Acacia gum 30 Example Carboxymethylcellulose 10 4 85 Alginic acid 30 Example Carboxymethylcellulose 10 4 86 Chitosan 30 Example Carboxymethylcellulose 10 4 87 Xanthan gum 30 Example Carboxymethylcellulose 10 4 88 Pectin 30 Example Carboxymethylcellulose 10 4 89 Agar 30 Example Pectin 10 4 90 Maltodextrin 30 Example Pectin 10 4 91 Dextrin 30 Example Pectin 10 4 92 Guar gum 30 Example Pectin 10 4 93 Arabic gum 30 Example Pectin 10 4 94 Acacia gum 30 Example Pectin 10 4 95 Alginic acid 30 Example Pectin 10 4 96 Chitosan 30

TABLE 5 Use amount of Natural polymer from Use ellagic which oligomer is amount acid Example derived (g) (g) Example Pectin 10 4 97 Carboxymethylcellulose 30 Example Pectin 10 4 98 Xanthan gum 30 Example Pectin 10 4 99 Agar 30 Example Agar 10 4 100 Maltodextrin 30 Example Agar 10 4 101 Dextrin 30 Example Agar 10 4 102 Guar gum 30 Example Agar 10 4 103 Arabic gum 30 Example Agar 10 4 104 Acacia gum 30 Example Agar 10 4 105 Alginic acid 30 Example Agar 10 4 106 Chitosan 30 Example Agar 10 4 107 Carboxymethylcellulose 30 Example Agar 10 4 108 Pectin 30 Example Agar 10 4 109 Xanthan gum 30 Example Hyaluronic acid 10 4 110 Maltodextrin 30 Example Hyaluronic acid 10 4 111 Dextrin 30 Example Hyaluronic acid 10 4 112 Guar gum 30 Example Hyaluronic acid 10 4 113 Arabic gum 30 Example Hyaluronic acid 10 4 114 Acacia gum 30 Example Hyaluronic acid 10 4 115 Alginic acid 30 Example Hyaluronic acid 10 4 116 Chitosan 30 Example Hyaluronic acid 10 4 117 Carboxymethylcellulose 30 Example Hyaluronic acid 10 4 118 Pectin 30 Example Hyaluronic acid 10 4 119 Agar 30 Example Hyaluronic acid 10 4 120 Xanthan gum 30

EXAMPLES 121 TO 138 Preparation of Oligomer Composite Containing Poorly Soluble/Insoluble Material

Dextrin and maltodextrin among natural polymer oligomers were added to distilled water according to a constant ratio as in the following Table 6. A reaction temperature was maintained in a range of 40° C. to 50° C., a pH was maintained in a range of 5 to 8 by using a pH adjuster, and an oligomer composite solution was formed by being stirred until the dextrin and maltodextrin were completely dissolved. The temperature and pH of the formed oligomer composite solution were maintained in ranges of 40° C. to 50° C. and 6.5 to 7.5, respectively. A predetermined amount of a poorly soluble/insoluble material was simply added to the oligomer composite solution or dissolved in an organic solvent to obtain a concentration of 1% to 50% and then the mixture was slowly added to the oligomer composite solution so as to allow the poorly soluble/insoluble material to be encapsulated in a hydrophobic cavity structure of the oligomer composite solution. The reaction solution was centrifuged and filtered to measure the weight of the unencapsulated and removed poorly soluble/insoluble material, an organic solvent such as ethanol was distilled by using a distiller for experimental groups including the organic solvent, and a supernatant or filtrate was powdered by using a freeze dryer to prepare an oligomer composite containing the poorly soluble/insoluble material.

TABLE 6 Added amount of Name of poorly poorly Use amount Use amount Use amount of soluble/insoluble soluble/insoluble of distilled Category of dextrin (g) maltodextrin (g) material material (g) water (g) Example 121 10 30 Amentoflavone 4 156 Example 122 10 30 Diosmetin 4 156 Example 123 10 30 Berginin 10 150 Example 124 10 30 Univestin 8 152 Example 125 10 30 Apigenin 4 156 Example 126 10 30 Resveratrol 4 156 Example 127 10 30 Isoflavones 8 152 Example 128 10 30 Salicylic acid 10 150 Example 129 10 30 Alpha lipoic acid 8 152 Example 130 10 30 Caffeine 10 150 Example 131 10 30 Tocopherol 8 152 Example 132 10 30 Docosahexaenoic 8 152 acid Example 133 10 30 Eicosapentaenoic 8 152 acid Example 134 10 30 Conjugated 8 152 linolenic acid Example 135 10 30 Ginkgo biloba 4 156 leaf extract Example 136 10 30 Red ginseng 4 156 extract Example 137 10 30 Soybean extract 8 152 Example 138 10 30 Epigallocatechin 10 150 gallate

[Experimental Method for Evaluating Solubility and Dissolution Stability of Examples]

The poorly soluble/insoluble material was added to the solutions having two types of the natural polymer oligomers dissolved therein and mixed during the preparation of the oligomer composites encapsulating the poorly soluble/insoluble materials in Examples 1 to 138, and then precipitates were dried during centrifugation or filtration to measure weights of insoluble precipitates.

Oligomer composite powders encapsulating the poorly soluble/insoluble material prepared in Examples 1 to 138 were weighed and put into distilled water to make a volume of 100 ml, and aqueous solutions were then prepared by stirring for 30 minutes. The prepared aqueous solutions were put into centrifuge tubes, in which the weights thereof had been previously measured, and centrifuged. Filtrates were removed and the tubes were dried in a vacuum drier at 60° C. for five days, and amounts of precipitates were then measured by measuring weight changes and solubilities of the oligomer composites containing a poorly soluble/insoluble material with respect to water were calculated. The presence of precipitates were visually observed while centrifuged supernatants were stored at 4° C. for zero week, one week, two weeks, three weeks, and four weeks.

The result of improvements in the solubility of the poorly soluble/insoluble material and the presence of precipitates with respect to Examples are presented in Tables 7 to 9.

TABLE 7 Input amount of oligomer composite Precipitate containing a amount poorly during soluble/insoluble Precipitate Poorly preparation material amount soluble/ of oligomer during during Presence insoluble composite redissolution redissolution Solubility Storage of Example material (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Example 1 Ellagic 0.03 2.0 0.0 20.0 4 weeks No acid Example 2 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 3 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 4 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 5 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 6 Ellagic 0.03 2.0 0.0 20.0 4 weeks No acid Example 7 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 8 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example 9 Ellagic 0.04 2.0 0.0 20.0 4 weeks No acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 10 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 11 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 12 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 13 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 14 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 15 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 16 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 17 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 18 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 19 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 20 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 21 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 22 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 23 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 24 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 25 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 26 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 27 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 28 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 29 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 30 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 31 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 32 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 33 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 34 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 35 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 36 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 37 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 38 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 39 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 40 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 41 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 42 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 43 acid ¹⁾precipitate amount of a poorly soluble/insoluble material undissolved during the preparation of an oligomer composite containing a poorly soluble/insoluble material ²⁾after the storage period of 4 weeks at 4° C., observation of the presence of precipitate

TABLE 8 Input amount of oligomer composite Precipitate containing a amount poorly during soluble/insoluble Precipitate Poorly preparation material amount soluble/ of oligomer during during Presence insoluble composite redissolution redissolution Solubility Storage of Example material (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 44 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 45 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 46 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 47 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 48 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 49 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 50 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 51 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 52 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 53 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 54 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 55 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 56 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 57 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 58 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 59 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 60 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 61 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 62 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 63 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 64 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 65 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 66 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 67 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 68 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 69 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 70 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 71 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 72 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 73 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 74 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 75 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 76 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 77 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 78 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 79 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 80 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 81 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 82 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 83 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 84 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 85 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 86 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 87 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 88 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 89 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 90 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 91 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 92 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 93 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 94 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 95 acid ¹⁾precipitate amount of a poorly soluble/insoluble material undissolved during the preparation of an oligomer composite containing a poorly soluble/insoluble material ²⁾after the storage period of 4 weeks at 4° C., observation of the presence of precipitate

TABLE 9 Input amount of oligomer composite Precipitate containing a amount poorly during soluble/insoluble Precipitate Poorly preparation material amount soluble/ of oligomer during during Presence insoluble composite redissolution redissolution Solubility Storage of Example material (g)¹⁾ (g) (g) (mg/ml) period precipitate²⁾ Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 96 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 97 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 98 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 99 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 100 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 101 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 102 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 103 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 104 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 105 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 106 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 107 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 108 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 109 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 110 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 111 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 112 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 113 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 114 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 115 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 116 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 117 acid Example Ellagic 0.03 2.0 0.0 20.0 4 weeks No 118 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 119 acid Example Ellagic 0.04 2.0 0.0 20.0 4 weeks No 120 acid Example Amentoflavone 0.03 2.0 0.0 20.0 4 weeks No 121 Example Diosmetin 0.05 2.0 0.0 20.0 4 weeks No 122 Example Berginin 0.05 5.0 0.0 50.0 4 weeks No 123 Example Univestin 0.06 4.0 0.0 40.0 4 weeks No 124 Example Apigenin 0.03 2.0 0.0 20.0 4 weeks No 125 Example Resveratrol 0.03 2.0 0.0 20.0 4 weeks No 126 Example Isoflavones 0.06 4.0 0.0 40.0 4 weeks No 127 Example Salicylic 0.01 5.0 0.0 50.0 4 weeks No 128 acid Example Alpha 0.02 4.0 0.0 40.0 4 weeks No 129 lipoic acid Example Caffeine 0.00 5.0 0.0 50.0 4 weeks No 130 Example Tocopherol 0.01 4.0 0.0 40.0 4 weeks No 131 Example Docosahexaenoic 0.01 4.0 0.0 40.0 4 weeks No 132 acid Example Eicosapentaenoic 0.01 4.0 0.0 40.0 4 weeks No 133 acid Example Conjugated 0.01 4.0 0.0 40.0 4 weeks No 134 linolenic acid Example Ginkgobiloba 0.02 2.0 0.0 20.0 4 weeks No 135 leaf extract Example Red 0.03 2.0 0.0 20.0 4 weeks No 136 ginseng extract Example Soybean 0.03 4.0 0.0 40.0 4 weeks No 137 extract Example Epigalloca 0.01 5.0 0.0 50.0 4 weeks No 138 techin gallate ¹⁾precipitate amount of a poorly soluble/insoluble material undissolved during the preparation of an oligomer composite containing a poorly soluble/insoluble material ²⁾after the storage period of 4 weeks at 4° C., observation of the presence of precipitate

As shown in Tables 7 to 9, with respect to the examples using two types of the natural polymer oligomers, it may be understood that when the poorly soluble/insoluble materials were added to the oligomer composite solutions to be encapsulated and then precipitates were almost not generated during centrifugation of the reaction solutions, and most of the poorly soluble/insoluble materials were encapsulated in the oligomer composites.

Precipitates were not generated even in the case that the prepared natural polymer oligomer composite powders containing the poorly soluble/insoluble material were redissolved and centrifuged, and precipitation was not observed after storing of centrifuged supernatants at 4° C. for 4 weeks.

Thus, when the poorly soluble/insoluble materials were encapsulated through the formation of oligomer composites by using oligomers derived from two types of hydrophilic natural polymers, solubilities of the poorly soluble/insoluble materials may be improved and dissolution stability may be increased. Therefore, the poorly soluble/insoluble materials may not only be used as a functional raw material of cosmetics industry, but application thereof may also be extended to other industries (food and medicine, etc.) requiring solubilization of the poorly soluble/insoluble materials.

According to a method of solubilizing a poorly soluble/insoluble material through formation of an oligomer composite of the present invention, an oligomer structure having a hydrophobic cavity structure is formed by physical bonding between molecules and a poorly soluble/insoluble material is encapsulated in the oligomer structure. Thus, dissolution stability of the poorly soluble/insoluble material in an aqueous solution may be increased.

Also, since precipitation due to redissolution of the poorly soluble/insoluble materials is prevented, the oligomer composite encapsulating the poorly soluble/insoluble material has excellent dissolution stability, and inherent biological activity of the poorly soluble/insoluble material may also be maintained as it is, because a chemical reaction is not accompanied.

The foregoing oligomer composite encapsulating the poorly soluble/insoluble material may improve water solubility and dissolution stability of an active substance.

Since the oligomer composite encapsulating the poorly soluble/insoluble material thus prepared has excellent dissolution stability, the oligomer composite may not only be used as a functional raw material of cosmetics industry, but application thereof may also be extended to other industries (food and medicine, etc.) requiring solubilization of the poorly soluble/insoluble materials.

A method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite according to embodiments will be described in detail with reference to the accompanying drawings. The invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein; rather, that alternate embodiments included in other retrogressive inventions or falling within the spirit and scope of the present disclosure can easily be derived through adding, altering, and changing, and will fully convey the concept of the invention to those skilled in the art. 

1. A method of solubilizing a poorly soluble/insoluble active material through formation of an oligomer composite, the method comprising: a first operation of preparing an oligomer composite having a cavity structure formed therein by mixing and dissolving oligomers derived from two types of hydrophilic natural polymers in water; and a second operation of adding a poorly soluble/insoluble material to the oligomer composite to encapsulate the poorly soluble/insoluble material in the hydrophobic cavity structure of the oligomer composite.
 2. The method of claim 1, further comprising, after the second operation: a third operation of removing a residual poorly soluble/insoluble material unencapsulated in the oligomer composite by filtration or centrifugation of a reaction solution; and a fourth operation of removing water and an organic solvent (when used) from the reaction solution having the residual material removed therefrom to dry.
 3. The method of claim 1, wherein the oligomers derived from the natural polymers are two selected from the group consisting of xanthan gum, acacia gum, guar gum, arabic gum, agar, alginic acid, chitosan, pectin, carboxyalkylcellulose, maltodextrin, dextrin, and hyaluronic acid.
 4. The method of claim 1, wherein the poorly soluble/insoluble material is any one selected from the group consisting of polyphenols, such as amentoflavone, ellagic acid, apigenin, berginin, diosmetin, univestin, resveratrol, isoflavones, and catechin, oily fatty acids, such as salicylic acid, alpha lipoic acid, caffeine, tocopherol, DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), and CLA (conjugated linolenic acid), and natural extracts containing a ginkgo biloba leaf extract, a red ginseng extract, and polyphenols.
 5. The method of claim 1, wherein a weight ratio of the natural polymer oligomers with respect to a total weight is in a range of about 1:1 to about 1:10, and the natural polymer oligomers are mixed within a temperature range of about 20° C. to about 80° C.
 6. The method of claim 1, wherein the poorly soluble/insoluble material is added in an amount range of about 0.1 wt % to about 99 wt % based on a total solid content and is mixed within a temperature range of about 20° C. to about 80° C.
 7. The method of claim 1, wherein the poorly soluble/insoluble material in the second operation is added by being dissolved in an organic solvent.
 8. The method of claim 7, wherein the organic solvent is any one selected from the group consisting of methanol, ethanol, acetone, THF (tetrahydrofuran), and AN (acetonitrile). 